Diuretics

Water issues

Prof. George Hsiao

Department of Pharmacology
School of Medicine
TMU

Nov., 2016
geohsiao@tmu.edu.tw

Goal: Understand the effects and

mechanisms of drugs on renal systems

Outline:
Background review
Functions of Renal System
Classification of Diuretic Therapy and
Drug Mechanisms
Adverse effects
www.patientlinx.com/home.cfm

Pathological conditions
The diseases of water imbalance
I. Dehydrogenation (low water level)
blood loss, burn, diabetes insipidus (CDI)

II. Edema (high water level)

congestive heart failure, hepatic failure
(ascites), nephrotic syndrome (anasarca),
stroke

Elevated water content in the tissue

CHF*

*****The strategy of treatment

Depletion of water

Renal functions
The role and value of kidney

To clean
(excrete, absorb and concentrate )
Polluted blood fluids (water)
useful: H2O, Na+, HCO3-, K+, Ca2+, Mg2+, glucose.
waste: urea, uric acid, metabolites

Anatomy of nephron and specific

renal tubule epithelial cells

The story of
tubes
F1
F3

F4
F2

F5

Renal tubule epithelial cells

Proximal tubule
epithelial cells

Na+
H2O
K+
Cl+

F1

Bicarbonate ions

Carbonic acid

Carbonate
anhydrase
Carbonate
anhydrase

Acetazolamide

F2

Furosemide; Ethacrynic acid

F3

Mutant Na+/Cl- cotransporter (NCC)

Gitelmans syndrome (-)
Pseudohypoaldosteronism type II (+)

Hydrochlorothiazide

F4

Mutant ENaC (epithelial sodium channel)

Liddles syndrome (+)
pseudohypoaldosteronism (-)

Aldosterone

Spironolactone; Triamterene/Amiloride

F5

Vasopressin (ADH): water channel (aquaporin-2)

ADH antagonist: tolvaptan

Carbonic anhydrase inhibitors

(acetazolamide)
(a) Chronic open-angle glaucoma
(aqueous humor production: HCO3-)
(b) Mountain sickness (=metabolic alkalosis)
(c) Short-term therapy (tolerance)

Loop diuretics (///)

(furosemide)

(a) Pulmonary edema (other effect: increase

renal blood flow by PGE)
(b) Hypercalcemia ()
(c) Acute and chronic hyperkalemia ()

 Thiazide (//;+)
(a) Hypertension (monotherapy; vasodilator
PGs) or with ACE inhibitor
(b) Congestive heart failure
(c) Edematous disorders
(d) Ca2+ nephrolithiasis ()/osteoporosis
(e) Most effective used in combination with
dietary salt restriction

Potassium-sparing diuretics
(spironolactone/triamterene)
(a) *Primary hyperaldosteronism
**Secondary hyperaldosteronism
(induction by CHF, cirrhosis, nephrotic
syndrome)
(b) Hypokalemia
(c) Cirrhosis with ascites
(d) Mild or moderate hypertension
(e) Female hirsutism (; spironolactone)

***Diuretic Resistance

Loop diuretic (chronic use: low efficacy)

Distal tubule cells:
Hypertrophy, hyperplasia, expression of Na+/Clcotransporter

The additional factors

High NaCl intake

Progressive renal failure
NSAIDs

(*) Solutions: combined use of a thiazide

Pharmacovigilance
Clinical problem and adverse effects
I. Carbonic anhydrase inhibitors
a. metabolic acidosis
b. drowsiness, fatigue
c. depression
d. paresthesia
e. hypersensitivity

 II. Loop diuretics

a. the electrolyte depletion phenomena
b. hyperlipidemia
c. vertigo and deafness (hearing deficits)
high rate of ototoxicity of ethancrynic acid
d. drug interaction
(indomethacin/warfarin/lithium)

 III. Thiazide diuretics

a. hypokalemia
b. ventricular dys-rhythmias (Mg2+ depletion)
c. hyper-uricemia (increasing proximal
tubular re-absorption and reducing tubular
secretion of urate)
d. hyponatremia (life-threatening: less than
100 mEq/L)
e. metabolic changes (hyperlipidemia,
hyperglycemia)
f. hypersensitivity

 IV. Potassium-sparing diuretics

A. Spironolactone
a. hyperkalemia
b. male:gynecomastia (), impotence
female: menstrual irregularities, lethargy
B. Triamterene/amiloride
a. hyperkalemia
b. elevated blood urea nitrogen and uric acid
c. renal stones
d. hypersensitivity

 (Main concept and summary)

Ref: 1. Basic &

2. Medmaps
3. Goodman
12 ed:

clinical pharmacology: p 251-271

for pathophysiology: p 111-141
& Gilmans The pharmacological basis of therapeutics,
p 671-716

Quiz 1:
A patient presents with chronic open
angle glaucoma. Which of the following
renal drugs might be prescribed as an
adjunct to lower intraocular pressure and
help manage his condition?
a. Acetazolamide
b. Amiloride
c. Furosemide
d. Spironolactone
e. Triameterne